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1 Pediatrics, Women and Children's Hospital of Buffalo, Buffalo, New York, United States
2 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
3 Physiology and Biophysics, SUNY at Buffalo, Buffalo, New York, United States
4 Pediatrics, University of California San Francisco, San Francisco, California, United States
5 Division of Neonatology, Children's Memorial Hospital, Chicago, Illinois, United States
6 Pediatrics, University of California, San Francisco, San Francisco, California, United States
* To whom correspondence should be addressed. E-mail: slakshmi{at}buffalo.edu.
Congenital cardiac defects associated with increased pulmonary blood flow (Qp) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Qp and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, twelve fetal lambs underwent in-utero placement of an aorto-pulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4-6 weeks of age. Electron paramagnetic resonance spectroscopy on fourth generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-Ethyl-2-thiopseudourea. Preconstricted fifth generation PA rings were relaxed with a NOS agonist (A23187), a NO donor (SNAP), polyethylene glycol conjugated superoxide dismutase (PEG-SOD), or H2O2. A23187, PEG-SOD and H2O2 mediated relaxations were impaired in shunt PA compared to controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A23187 and SNAP in shunt but not control PA. Inhibition of NOS with L-nitroarginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A23187, SOD and H2O2. We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H2O2, a pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Qp.
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